Pharma Manufacturing

Pharmaceutical processors have begun to wield some new tools, nailing down new efficiencies and better drugs in the process.

Maslow wrote, “I suppose it is tempting, if the only tool you have is a hammer, to treat everything as if it were a nail.” For decades, Pharma’s been engineering its own “hammer,” creating development and production methodologies that tended to treat every potential drug candidate like the proverbial nail. To many, Pharma’s hammer became too heavy to wield, not only inefficient at driving Pharma’s traditional solid-dose nails but increasingly ineffective at addressing quality issues at the manufacturing level for biopharmaceuticals. Since FDA promulgated Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach, drug makers have invested in its principles slowly if not grudgingly — with some more enthusiastic…

Chad Juros inspired the crowd with his story and his magic, but closed his talk by saying, "The true magicians in this world are those who are bringing these miracle treatments and services that saved my life."

The start of the 2015 Annual Meeting was magic…literally. Chad Juros, founder of the Spread the Magic Foundation, a nonprofit corporation that performs magic to raise money for pediatric cancer patients, started the three-day conference with a message of positivity and gratitude. A childhood cancer survivor and medical miracle, Chad’s father taught him magic as a survival tactic, a way of diverting attention from the negative to the positive in his life. But as accomplished as he is, Chad closed his speech by admitting he, in fact, does not know “real” magic. “The true magicians in this world are those who are bringing these miracle treatments and services that saved my life,” Chad said. “I’m living proof that the hard work…

Pharma can take inspiration from industries with mature quality systems and advanced quality capabilities

Quality has a special meaning in pharmaceuticals, where production or distribution errors can jeopardize human life. But other industries face similar challenges, and some have developed sophisticated quality systems. As pharmaceutical companies look for ways to improve their quality practices and performance, they can take ideas from these quality leaders and adapt them for pharma.
Quality can be defined in various ways, from “fitness for purpose” to “meeting customer expectations” to predictability in statistical terms. Each industry understands quality differently, and priorities depend on the specifics of products and markets. In the automotive industry, for instance, companies generally define quality as the ability to meet…

Advancing aseptic processing through the use of robot technology

Josh Russell, AST’s Life Science project manager, has been an advocate for advancing aseptic processing through the use of robot technology for years, writing about its benefits and exploring their application in their customer’s solutions. According to Russell, aseptic manufacturing generally entails often repetitive activity that requires a high degree of reproducibility in order to create a high-quality product. He asserts that robots are the ideal platform to perform the highly accurate, repeatable operations demanded by aseptic processing operations. These non-organic automatons have the distinction of being able to operate where no man should or can. “This becomes particularly important in applications that require…

If your equipment is not ready, it’s time to get it ready

Pharmaceutical counterfeiting is on the rise — and a growing health and safety issue with deep consequences for consumers and drug manufacturers alike. A number of factors contribute to counterfeiting, including:
• Increased involvement of under-regulated wholesalers and repackagers in the supply chain,• Proliferation of online pharmacies,• Counterfeiting technology advancements, and• Increased importation of gray-market medicines.
To combat counterfeiting, pharmaceutical manufacturers are putting serialization processes in place — whereby each item is assigned and marked with a unique serial number. Drug makers can then identify and track each unit throughout the supply chain, providing greater visibility and traceability.
But…

The optimization and scale-up of wet granulation processes is often an essential step in the commercialization of oral solid dosage (OSD) products. Granulation enables the preparation of an optimized blend for tableting in which small quantities of highly potent active ingredients (APIs) are stably and homogeneously distributed. Furthermore, granule properties can be manipulated to control, for example, the flowability of the blend and its compressibility. In these ways granulation underpins the manufacture of high-quality tablets with consistent dose uniformity.Wet granulation, and in particular high shear wet granulation, is the technology of choice for many OSD production processes. Compared with alternative methods, high shear…

Novel technologies open a new avenue for developing the future
of pharmaceutical manufacturing

Pharmaceutical manufacturing has been performed using batch technologies for more than a century. While most other manufacturing industries use continuous operations combined with advanced process control and automation, the pharmaceutical industry…

The optimization and scale-up of wet granulation processes is often an essential step in the commercialization of oral solid dosage (OSD) products. Granulation enables the preparation of an optimized blend for tableting in which small quantities of highly potent active ingredients (APIs) are stably and homogeneously distributed. Furthermore, granule properties can be manipulated to control, for example, the flowability of the blend and its compressibility. In these ways granulation underpins the manufacture of high-quality tablets with consistent dose uniformity.Wet granulation, and in particular high shear wet granulation, is the technology of choice for many OSD production processes. Compared with alternative methods, high shear…

Closed-loop systems help pharmaceutical manufacturers save water and energy

While the pharmaceutical industry continues on its road to recovery, sustainability will remain a priority for pharmaceutical manufacturers as they strive for profitable growth. One way many can make significant headway toward true sustainability — and improve the bottom line — is through the use of advanced, closed-loop process cooling technology specifically designed to lower water consumption and save energy.
Process cooling efficiency should be on the front burner rather than the afterthought it often is. Doing so is particularly important today given increasing concern over water use by pharmaceutical manufacturers and other companies that use water-intensive processes to make and deliver products. Following are some…

Recent

When the FDA finds significant departures from good clinical practice, those findings are seldom reflected in the peer-reviewed literature, even when there is evidence of data fabrication or other forms of research misconduct.

A new New York University analysis found that when the FDA's finds serious problems with how medical researchers collect their data, the peer-reviewed literature often doesn't mention it.Using documents and data from 1998 to 2013, researchers identified 57 clinical trials that received an “official action indicated” violation for reasons including inadequate or inaccurate recordkeeping, false information and poor patient safety.
And yet, among the 78 published analyses of data from those sanctioned trials, only three noted violations.
One example was found where the entire clinical trial was deemed unreliable by the FDA, and the published paper failed to make mention of this. In another example, the published paper claimed all…

New xCELLigence RTCA CardioECR is the first platform for simultaneous measurement of Cardiomyocyte Contractility and Electrophysiology

Responding to the need for more predictive preclinical assays for cardiac liability, ACEA Biosciences introduced a “ground-breaking” device the company describes as “next generation.” Designated the xCELLigence RTCA CardioECR System, it is…

The U.S. attorney’s office has charged Barry Cadden, owner of New England Compounding Center and Glenn Chin, head pharmacist, with 25 acts of second-degree murder in seven states.

The U.S. attorney’s office has charged Barry Cadden, owner of New England Compounding Center and Glenn Chin, head pharmacist, with 25 acts of second-degree murder in seven states in relation to the production of tainted drugs that killed 64 people and sickened hundreds with fungal meningitis in the fall of 2012.
Attorneys claim that the senior execs at the now-closed N.E.C.C. knew of filthy conditions and improper sterility testing.A total 14 people were charged in a 131-count indictment, many of them N.E.C.C. pharmacists. The charges include mail fraud, conspiracy, racketeering and violation of the Food, Drug and Cosmetic Act. Only Cadden and Chin were charged with murder.
Both men plead not guilty in federal court on Wednesday.
Read…

Chad Juros inspired the crowd with his story and his magic, but closed his talk by saying, "The true magicians in this world are those who are bringing these miracle treatments and services that saved my life."

The start of the 2015 Annual Meeting was magic…literally. Chad Juros, founder of the Spread the Magic Foundation, a nonprofit corporation that performs magic to raise money for pediatric cancer patients, started the three-day conference with a message of positivity and gratitude. A childhood cancer survivor and medical miracle, Chad’s father taught him magic as a survival tactic, a way of diverting attention from the negative to the positive in his life. But as accomplished as he is, Chad closed his speech by admitting he, in fact, does not know “real” magic. “The true magicians in this world are those who are bringing these miracle treatments and services that saved my life,” Chad said. “I’m living proof that the hard work…

PerkinElmer will provide on-site staff and training as well as scientific application support, a new offering to JLABS residents

Lab solutions provider PerkinElmer Inc. announced its collaboration with Johnson & Johnson Innovation to equip its JLABS @South San Francisco (JLABS @SSF) life science incubator with instruments and lab services to address the research needs of resident startups. Janssen Labs (ostensibly JLABS) is the no-strings-attached incubator network that Johnson & Johnson says, is home to more than 70 life science companies. JLABS @SSF is the newest member of the J&J Innovation JLAB network which includes an established San Francisco location as well as facilities in San Diego, Boston and most recently Houston.Companies seeking to avail themselves of the infrastructure and support apply and go through a selection process which evaluates…

Kythera is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel prescription products for the aesthetic medicine market. The company’s objective is to develop prescription products using an approach that relies on the scientific rigor of biotechnology to address unmet needs in a rapidly growing market. Kythera’s initial focus is on facial aesthetics — the market’s largest segment. The company’s drug for the reduction of submental fat is currently in late-stage clinical development.
SYSTEM TO IMPROVEKythera sought a system to improve clinical document management and facilitate business processes for the development of its newest product candidate. The company had 26…

According to Johnson & Johnson, the Geel, Belgium facility produces 54 different types of APIs and three semi-finished APIs, via more than 350 different synthesis steps. In total, the Geel produces +/- 60 % of the total small-molecule API volume within the company. Johnson & Johnson recently updated its Manufacturing Execution System (MES) to PAS-X V3.1.5. The Geel site plays a key role for J&J: there, PAS-X is in operation as full-blown MES in several areas of its API manufacturing lines and warehouse operations. About 300 employees use the system, says Werum, to achieve operational excellence and transparency at the 450.821 m2 site.
“Johnson & Johnson has already implemented Werum’s PAS-X in some plants,” says…

Recent

The memorandum of understanding establishes a process of disclosure and sharing of their respective databases

The U.S. Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) announced they have signed a Memorandum of Understanding to share data on pesticides and toxic substances. This will allow the agencies to more easily share information about risks to the public and the environment.
According to a press release, the FDA and EPA have complementary roles in their regulatory authority for some substances incorporated into food (including animal food and feed), animal drugs and cosmetics. The FDA protects and promotes the public health by enforcing the Food, Drug, and Cosmetic Act, and several related public health laws. EPA manages the pesticides and toxic substances programs under the Federal Insecticide, Fungicide, and…

A new report from FireEye says that a cybercriminal group has been stealing data from more than 100 organizations, mainly targeting publicly traded health care, pharmaceutical and biotechnology companies, to gain insider knowledge to manipulate the stock market.

A new report from U.S. security firm FireEye says that a cybercriminal group known as FIN4 has been stealing data from more than 100 organizations, mainly targeting publicly traded healthcare, pharmaceutical and biotechnology companies, to gain insider knowledge to manipulate the stock market.
FireEye reports that the cybercriminals have targeted the email accounts of individuals privy to the most confidential information of more than 100 companies. According to the report, "FIN4 appears to have a deep familiarity with business deals and corporate communications, and their effects on financial markets. Operating since at least mid-2013, FIN4 distinctly focuses on compromising the accounts of individuals who possess non-public…

Specializing in pain management and fungal disease, Janssen-Cilag Farmacêutica Ltda., is a research-based pharmaceutical company located in São Paulo, Brazil. Janssen-Cilag is a member of the Johnson & Johnson family of companies — the world’s largest personal care and health products manufacturer with worldwide annual sales totaling $63.7 billion. In an effort to streamline business processes, Janssen-Cilag’s Global Pharmaceutical Supply Group (GPSG) Brazil recently adopted a comprehensive enterprise integration solution. As part of its quest for a state-of-the-art IT implementation, GPSG Brazil took advantage of the latest technological advancements from Thermo Scientific in its São José dos Campos laboratory complex in…

Recent

Kemwell Biopharma announced that its oral solids manufacturing facility located in Bangalore, India has successfully completed its second U.S. Food and Drug Administration inspection.

Kemwell Biopharma, a global bio/pharmaceutical contract development and manufacturingcompany, announced that its oral solids manufacturing facility located in Bangalore, India has successfully completed its second U.S. Food and Drug Administration inspection.
This audit took place for an ANDA filed for a customer. On completion of the inspection, the FDA inspector concluded that the facility, systems and practices comply with U.S. FDA requirements and no observations were reported on Form 483.
The state-of-the-art oral solids facility started cGMP production in 2008 and is designed to produce 5 billion tablets and capsules annually. The facility has high flexibility built-in to manage batch sizes ranging from 10kg to 1000kg. Kemwell has…

Pfizer expects to receive a $200 million upfront payment from Lilly in accordance with their collaboration agreement

Pfizer Inc. and Eli Lilly and Company are planning to resume the Phase 3 clinical program for tanezumab. As a result, Pfizer expects to receive a $200 million upfront payment from Lilly in accordance with their collaboration agreement, according to a press release.
This announcement follows a decision by the U.S. Food and Drug Administration (FDA) to lift the partial clinical hold on the tanezumab development program after a review of nonclinical data characterizing the sympathetic nervous system response to tanezumab, the release said. The data were submitted to the FDA in February 2015.
In the prior clinical studies of more than 11,000 patients, tanezumab demonstrated clinically meaningful efficacy vs. placebo and other select commonly…

Is the FDA allowed to approve a use for a treatment for which a drug maker did not seek approval?

Japan's Otsuka Pharmaceuticals is suing the U.S. FDA, claiming the agency illegally broadened the indication for its top-selling Abilify antipsychotic, opening the door to generic competition in the process.
According to the WSJ, the FDA approved Abilify for treating children with Tourette Syndrome last December, a move which delayed generics because the new indication gave Otsuka another seven years of exclusive marketing rights under an orphan designation.
Last month, the FDA notified Otsuka that the added indication for treating Tourette Syndrome would apply to adults as well as children.
By broadening Abilify's indication to include adults, Otsuka argues the FDA will trigger a labeling change that will allow generic competition.

A CPV approach based only on statistical tools addresses only the operational level of the system; management needs to be involved

A company gets a 483 warning letter which, among other things, criticizes the company’s continued process verification (CPV) approach. The observations include inadequate sampling plans, wrong statistical methods used, and company employees do not understand the statistical methods being used. Only a single quality engineer knows how the tools are being used.
So the company scurries about figuring out how to respond including the adoption of better procedures and more clearly explaining the methods being used. So what is the problem here? Who is at fault? The quality engineer? His supervisor? The plant manager? How should this situation be remedied?
The answer is: All of the above with the major portion the responsibility being that of…

Chad Juros inspired the crowd with his story and his magic, but closed his talk by saying, "The true magicians in this world are those who are bringing these miracle treatments and services that saved my life."

The start of the 2015 Annual Meeting was magic…literally. Chad Juros, founder of the Spread the Magic Foundation, a nonprofit corporation that performs magic to raise money for pediatric cancer patients, started the three-day conference with a message of positivity and gratitude. A childhood cancer survivor and medical miracle, Chad’s father taught him magic as a survival tactic, a way of diverting attention from the negative to the positive in his life. But as accomplished as he is, Chad closed his speech by admitting he, in fact, does not know “real” magic. “The true magicians in this world are those who are bringing these miracle treatments and services that saved my life,” Chad said. “I’m living proof that the hard work…

Pharma can take inspiration from industries with mature quality systems and advanced quality capabilities

Quality has a special meaning in pharmaceuticals, where production or distribution errors can jeopardize human life. But other industries face similar challenges, and some have developed sophisticated quality systems. As pharmaceutical companies look for ways to improve their quality practices and performance, they can take ideas from these quality leaders and adapt them for pharma.
Quality can be defined in various ways, from “fitness for purpose” to “meeting customer expectations” to predictability in statistical terms. Each industry understands quality differently, and priorities depend on the specifics of products and markets. In the automotive industry, for instance, companies generally define quality as the ability to meet…

If your equipment is not ready, it’s time to get it ready

Pharmaceutical counterfeiting is on the rise — and a growing health and safety issue with deep consequences for consumers and drug manufacturers alike. A number of factors contribute to counterfeiting, including:
• Increased involvement of under-regulated wholesalers and repackagers in the supply chain,• Proliferation of online pharmacies,• Counterfeiting technology advancements, and• Increased importation of gray-market medicines.
To combat counterfeiting, pharmaceutical manufacturers are putting serialization processes in place — whereby each item is assigned and marked with a unique serial number. Drug makers can then identify and track each unit throughout the supply chain, providing greater visibility and traceability.
But…

A well-designed, reliable raw material storage and conveyance environment can make or break a pharmaceutical manufacturing environment. Raw material storage and conveyance is fundamental to quality assurance and profitability. Increasingly, this environment also has become integral to the rigorous regulatory requirements for tracking and tracing products throughout the supply chain. To meet quality and standardization objectives, a design solution must be based on an overview of the entire process from delivery of raw materials to the manufacturing site to delivery of product ingredients to the manufacturing line. The correct design basis is predicated, particularly, on an understanding of raw material characteristics and facility…

Manufacturing HP active pharmaceutical ingredient drugs is a challenge best met with a thorough assessment of risk and a robust containment strategy

Approximately 25 percent of drugs in development worldwide are classified as highly potent, with this percentage expected to grow over the coming years. A compound is generally classed as highly potent if it has an occupational exposure limit (OEL) of ≤10μg/m3, a daily therapeutic dose of ≤10mg/day or if a 1 mg/kg/day dose produces serious toxicity in laboratory animals. While such highly potent compounds can have significant benefits in the treatment of certain medical conditions, they present substantial challenges to the pharmaceutical industry.
These challenges include:
• Can personnel and the environment involved in the manufacture of high potency products be protected; • Can adequacy of controls preventing contamination of…

Closed-loop systems help pharmaceutical manufacturers save water and energy

While the pharmaceutical industry continues on its road to recovery, sustainability will remain a priority for pharmaceutical manufacturers as they strive for profitable growth. One way many can make significant headway toward true sustainability — and improve the bottom line — is through the use of advanced, closed-loop process cooling technology specifically designed to lower water consumption and save energy.
Process cooling efficiency should be on the front burner rather than the afterthought it often is. Doing so is particularly important today given increasing concern over water use by pharmaceutical manufacturers and other companies that use water-intensive processes to make and deliver products. Following are some…

The new investment in biotechnology will create up to 100 new jobs

AbbVie plans to expand of one of its existing sites in Barceloneta with an estimated investment of $30 million. The expansion will add to Puerto Rico’s capabilities as a manufacturing destination for biotechnology and is expected to create up to 100 new jobs over the next two years, according to a press release.“AbbVie’s expansion in Barceloneta is very important for us, as this site is one of the world's most advanced biopharmaceutical facilities, contributing to our island's growing reputation as a biotech hub,” said Puerto Rico governor Alejandro García Padilla.
According to Stephen Muldoon, vice president of engineering and operations for AbbVie, “This investment demonstrates our commitment to Puerto Rico as a key element of…

Closed-loop systems help pharmaceutical manufacturers save water and energy

While the pharmaceutical industry continues on its road to recovery, sustainability will remain a priority for pharmaceutical manufacturers as they strive for profitable growth. One way many can make significant headway toward true sustainability — and improve the bottom line — is through the use of advanced, closed-loop process cooling technology specifically designed to lower water consumption and save energy.
Process cooling efficiency should be on the front burner rather than the afterthought it often is. Doing so is particularly important today given increasing concern over water use by pharmaceutical manufacturers and other companies that use water-intensive processes to make and deliver products. Following are some…

Kemwell Biopharma announced that its oral solids manufacturing facility located in Bangalore, India has successfully completed its second U.S. Food and Drug Administration inspection.

Kemwell Biopharma, a global bio/pharmaceutical contract development and manufacturingcompany, announced that its oral solids manufacturing facility located in Bangalore, India has successfully completed its second U.S. Food and Drug Administration inspection.
This audit took place for an ANDA filed for a customer. On completion of the inspection, the FDA inspector concluded that the facility, systems and practices comply with U.S. FDA requirements and no observations were reported on Form 483.
The state-of-the-art oral solids facility started cGMP production in 2008 and is designed to produce 5 billion tablets and capsules annually. The facility has high flexibility built-in to manage batch sizes ranging from 10kg to 1000kg. Kemwell has…

New York-based Synergy Pharmaceuticals, developer of gastrointestinal disorder drugs, is talking to advisers about a potential sale of the company, according to Bloomberg sources.

New York-based Synergy Pharmaceuticals, developer of gastrointestinal disorder drugs, is talking to advisers about a potential sale of the company, according to Bloomberg sources.
Earlier this month, Salix -- which competes with Synergy in the gastrointestinal field -- was purchased by Valeant Pharmaceuticals for $10 billion.
Bloomberg sources say the sale of Synergy may depend on the results of a late-stage trial of IBS drug plecanatide, which should be announced in May.
Read the Bloomberg article

This comes on the heels of GSK announcing 150 layoffs in Pennsylvania

GlaxoSmithKline announced another round of layoffs affecting 180 workers in North Carolina, according to an article in the Triangle Business Journal. Eliminated positions were in sales, marketing, operations and other managerial, technical and support roles, the article said. This comes on the heels of GSK announcing 150 layoffs in Pennsylvania. Read the full story

Is the FDA allowed to approve a use for a treatment for which a drug maker did not seek approval?

Japan's Otsuka Pharmaceuticals is suing the U.S. FDA, claiming the agency illegally broadened the indication for its top-selling Abilify antipsychotic, opening the door to generic competition in the process.
According to the WSJ, the FDA approved Abilify for treating children with Tourette Syndrome last December, a move which delayed generics because the new indication gave Otsuka another seven years of exclusive marketing rights under an orphan designation.
Last month, the FDA notified Otsuka that the added indication for treating Tourette Syndrome would apply to adults as well as children.
By broadening Abilify's indication to include adults, Otsuka argues the FDA will trigger a labeling change that will allow generic competition.

Johnson & Johnson subsidiary McNeil Consumer Healthcare pleaded guilty on Tuesday to selling liquid medicine contaminated with metal and agreed to pay $25 million to resolve the case, says the U.S. Department of Justice.
According to court documents, on or about May 1, 2009, McNeil received a complaint from a consumer regarding the presence of “black specks in the liquid on the bottom of the bottle” of Infants’ Tylenol. The foreign material was later identified as nickel/chromium-rich inclusions, which were not intended ingredients in the drug.
In connection with receiving this consumer complaint, McNeil did not initiate or complete a Corrective Action Preventive Action (CAPA) plan, as alleged in the charging document. The…

In text, illustrations, and video, Bren Kindelsperger makes the case for continuous wet mass granulation as an alternative to traditional methods of tablet and pill formulation.

Note: To watch a video of the processes described in this article, click here. For a previous article by this author on the potential of continuous processes in pharma, read here.

Wet mass granulation is the basis of most tablet formulations in the pharmaceutical industry. It is, at present, a time consuming and multi-stage process that involves considerable time, energy consumption, operational steps, and machinery. Much of the effort and time involved is based on the assumptions that are used in how the process must be conducted, as opposed to how it can be simplified and the operation simplified. Developing an alternative process that would simplify and streamline the process would offer significant improvements for the pharmaceutical industry.

The benefits of continuous processing are well known (References). FDA draft guidance encourages innovation in manufacturing technology, including continuous processing. The basic principle of Quality by Design (QbD) is that “the quality cannot be tested into a product, but must be built in by design”. Specifically, the draft guidance cites: “Facilitating continuous processing to improve efficiency and manage variability”.

Although the perceived benefits and advantages of Continuous Processing are known, the lack of applications in the pharmaceutical industry and the historical emphasis on batch type processing, has meant reluctance to view continuous processing as a legitimate option to consider. One method to clarify the possible role of continuous processing in the Pharmaceutical Industry would be to document a continuous process production demonstration of a widely used process.

Wet mass granulation is one process that is widespread in pharmaceuticals that would be understood in concept but also would provide an objective way to show comparative methods between batch preparation and continuous processing.

Background of Wet Mass Granulation:

About 70% of the pharmaceutical products are solid dosage forms (tablets, capsules, oral powders and powders for solutions or suspensions). The efficiency of tableting, encapsulation and powder filling processes depends on the quality of the granulation which can be processed on high speed machines. Adequate performance requires a granulation process that insures good quality granulation suitable for these processes. Beside direct compression, the granulation processes of choice have been: wet granulation or roller compaction. Both of these granulation processes utilize multiple unit operations, requiring additional pieces of equipment for each unit operation. In addition, many granulating unit operations require critical control of variables. Recently, the use of Process Analytical Technology (PAT) has made it possible to better control these variables, but it has not been very easy or simple or inexpensive. Inherently, because they involve multiple steps done in sequence, these processes do not easily lend themselves to the possibility of continuous processing.

Objective

Performing wet mass granulation on a continuous basis would simplify the process, reduce the time involved, reduce human error, batch deviation or loss, reduce the number of steps and machinery involved, and significantly reduce the cost to perform this operation. At the same time, it is necessary to achieve equal to or better than product requirements that are necessary for volume production of tablets and the tablet press concept. This paper will present the findings of a demonstration conducted on a wet mass granulation process that will show the ability to achieve the desired objectives.

Background

The most common steps involved in the wet granulation process are:

1. Preparation of pre-blend.2. Addition of granulating fluid or solution/suspension3. Mixing or kneading to create wet mass or wet granules4. Drying of wet granules5. Sizing of dry granules6. Mixing of other excipients7. Mixing of lubricant

It is possible to carry out several of these steps in a high shear or a planetary mixer followed by tray or fluid bed drying. Another alternative that will combine several steps is to use a fluid bed granulator, but a granule sizing operation is still needed as well as the mixing operations for excipients and the lubricant. Most of the efforts directed towards continuous wet granulation have been directed towards improvements on the equipment side of the equation in order to overcome the challenges involved in traditional wet granulation. However, little or no innovation has been directed towards removing the road blocks in the wet granulation process that impede the conversion to continuous processing.

Defining the Existing Process

The process involves mixing dry powders, consisting of excipients, and active pharmaceutical ingredients, with a liquid binder causing the wet mass to agglomerate into granules. Drug fillers and/or binders are first mixed to make sure of mixture homogeneity. At this point, the resulting granulated mixture is combined with water in the range of 10-20%, and again mixed to insure homogeneity. The next step would be to dry the resulting mixture to reduce the moisture content down to the single digit level. The next step would be to add moisture absorbing agents and blending those into the granulated mixture. Next would be to add disintegrants, followed by a blending operation and a final addition of lubricants, and an additional combining operation. This process, commonly used, is the basis for most pill and/or tablet formulations. That process, utilizes a number of manufacturing processes and steps along with a number of different types of machinery that are involved in that process. In addition to labor, capital cost, and time of manufacture, there are also significant energy costs, particularly in the drying cycle, for the product.

Figure 1 outlines the existing process.

While not all tablet formulations may follow this exact sequence and some may have significantly different percentages of the different ingredients. They may have different ingredients or may have single or multiple ingredient additions in the process. However, the wet granulation process follows this general type of sequence.

Drying and sizing are the major road blocks in the path of development of a truly continuous wet granulation process. In addition, a significant PAT investment is needed to control the granulation end point, moisture removal, and sizing of such granules. It would be possible to convert wet granulation to a continuous process, if it was possible to eliminate drying and sizing steps from wet granulation as well as make the granulation end point less sensitive to shear and residence time.

The Continuous Low Moisture Wet Mass Granulation addresses these areas and opens up the possibility of significant change in the process. In this process, only the necessary amount of water needed to create granules is added, but not any excess water which would need to be removed by drying; therefore no drying step needed. The amount of water used in the process is usually 1-4%, of the finished product and thus the agglomeration process is not very sensitive to shear and residence time. This process creates only small, relatively spherical granules that do not need sizing. As a result, this process only has two unit operations, agglomeration and mixing

Overview of Demonstration

The Continuous Processor manufactured by Readco Kurimoto was utilized as the mixing equipment for performing all these operations described above. The powders were introduced as dry ingredients and metered through gravimetric screw feeders mounted on precision loss-in-weight scales for closed-loop verification. The liquids were metered through Peristaltic pumps using downstream coriolis flowmeters for closed-loop verification. The entire blending process was controlled through a central touchscreen operator interface containing all operation, recipe and tuning parameters for both the Continuous Processor and ancillary metering equipment.

The continuous mixing machine is a twin-shaft co-rotating device which contains individual mixing elements that intermesh. These mixing elements can be interchanged to make mixing concentrations and/or characteristics to be tailored to specific situations and to affect particular chemical reactions. By trading time for intensity, all of the combining operations can be done in a very small space, and in a very short time frame. This process also reduces the discharge of costly energy sources to the atmosphere.

The machine used for the test has a mixing barrel approximately 35-inches long and is powered by a 5-HP motor, capable of running at speeds from 25 to 300 RPM.

Test Setup

Two continuous mixing machines of a small production size were setup in sequence, with the output of the first machine fed directly into the input port of the second machine. The first mixing machine was fed a small percentage of water (1-4% by weight), and the binder which mixed with a blend of lactose and PVP12. The moisture absorbing material, a blend of Aperoperl 300 and Avicel LM200 was also fed into the mid point entry of the first machine. The resulting mixture was generated at the throughput rate of 80#/hr. with a total cycle time of less than one minute. That resultant was then fed directly into the inlet of the continuous mixing machine #2 where the disintegrant (Polyplasdone XL) was added. The final ingredient is a lubricant (Magnesium Sterate blend), and this ingredient was metered into the mid-port feed port of the second continuous machine.

Figure 2 is a schematic of the production set up.

The feeders and pumps were calibrated to specific formula levels and feed rates prior to testing. Graphs were generated from the data collected during calibration, and the feed rates quantified to match the intended levels. Total foot print area consumed by this production demonstration was 8’ by 8’ by 8’.

The blending control system was designed to integrate all discrete components onto a single Allen-Bradley ControlLogix PLC hardware platform for ease of use, maintainability, and reliable operation. All process temperatures are monitored directly by a PLC thermocouple card. All shaft speeds are monitored directly by a PLC tach encoder card. Both the powder and liquid loss-in-weight scales are monitored directly from load cell amplifiers by the PLC over an Ethernet IP network. All valves and motors are controlled directly for the PLC I/O cards.

The result of the test was a product throughput rate of 80#/hr. This production rate was achieved using the smallest size production machinery manufactured by the company. Larger scale production rates are available using larger capacity machinery. The total cycle time for this process from entry of the first ingredient to collection of the finished product was less than a minute and a half. The total horse power draw during operation was less than 2 HP. The resulting material was judged to be well mixed, uniform, and free flowing. A result of the table testing capability of the finished material indicated that it satisfied all requirements of the wet mass granulation properties for tablet compaction.

This type of machinery used and the results of this process have been reviewed in the literature, and this demonstration is confirmation of the use of the continuous process for this and other powder processes. The ability to process powders continuously, with low moisture content, and with multiple ingredient additions during the process, is a significant factor in process improvement in the powder processing industry.

Conclusions

There are several factors that can be concluded as a result of the success of this demonstration. The continuous mixing machine is capable of “wetting” or homogenously mixing powders when the per centage of moisture addition is in the 1 to 4% range. This is accomplished be simply adding only the desired level of moisture directly to the mixing chamber during operation, and achieving a consistent, homogenous result.

The continuous mixer is doing the work of this process in a small, controlled chamber so that the work energy required is vastly reduced. Because the “wetting agent” is only introduced at the desired level for the finished product and there is no need for a drying step in processing, the Horse Power consumption for the entire process is less than 2 HP for 80 LBS/HR.

The use of gravimetric feeders along with the commensurate electronic control system, demonstrates that it is possible to attain significantly high standards for accuracy of feed rates. The advertised standard from major feeder suppliers is “1/4% gravimetric accuracy @ 2-sigma based on 60-second catches.” The process is totally scalable up to through put levels of 60,000 lbs/hr, by the use of larger machines. The use of existing technology in control systems has demonstrated the ability to control the results to meet industry standards for control.

It is possible to consider continuous wet mass granulation as an alternative to the existing method to produce tablet and pill formulations. This potential could allow manufacturers significant cost and productivity savings and streamline operational concerns.

A mix of feature articles and current new stories that are critical to staying up-to-date on the industry, delivered to your inbox. Choose from an assortment of different topics and frequencies. Subscribe Today.